Vincristine, an alkaloid obtained from the plant, Vinca rosea Linn, has been widely employed in the treatment of a variety of solid tumors, lymphomas, and lymphocytic leukemia. Due to its relative lack of myelosuppression, vincristine has been included in numerous combination chemotherapy programs. However, neurotoxicity is a frequent side-effect and findings commonly include loss of reflexes, paresthesias, constipation, and muscle weakness. Discontinuation of the drug and reduction of the frequency of administration and/or dose are currently the only methods of altering these side-effects. During the past three years a variety of drugs have been tested in an animal model of vincristine-induced toxicity. DBA/2 20 gram male mice have been injected intraperitoneally with vincristine every other day until development of neurotoxicity as indicated by disturbance of gait and, subsequently, death. Approximately 20 agents potentially capable of antagonizing vincristine have been screened. Of these, glutamic acid has resulted in a significant reduction of vincristine toxicity in mice which appears to be dependent upon the schedule of administration; lack of inhibition of vincristine's antitumor effect has been observed in mice bearing both P-388 and P-1534 murine leukemia. Subsequently, glutamic acid has been investigated in a clinical trial; preliminary results have been encouraging. Other agents appearing to antagonize vincristine-induced toxicity in the mouse model include: tryptophan, phenylalanine, folinic acid and pyridoxine; further investigations including determination of the optimal schedule of administration, interaction with vincristine in the tumor bearing model, and statistical analysis are required. Finally, clinical trials of agents found to antagonize vincristine-induced host toxicity but not its antitumor effect will be undertaken. If methods can be developed to control vincristine-induced neurotoxicity, it is anticipated that greater patient comfort and more effective treatment with this agent will be possible. This research is an integral part of the multidisciplinary Oncology Research Center at the Bowman Gray School of Medicine.